Tumor shrinkage occurred in more than 90% of patients, and 73% achieved a complete or partial response at a median follow-up of 20.4 months, while median survival exceeded 20 months, which the researchers say demonstrates superior antitumor activity to that expected from axitinib or PD-1 pathway inhibitor monotherapy alone.

“On the basis of the results of this phase 1b trial, the US Food and Drug Administration granted the axitinib–pembrolizumab combination a breakthrough status,” they report in The Lancet Oncology.

“A randomised phase 3 trial (NCT0285331) comparing the combination to sunitinib monotherapy is underway, and if this trial confirms the results for the combination reported here, it is likely to lead to a new first-line treatment option for patients with advanced renal cell carcinoma.”

A dose-finding phase involving 11 patients was followed by a dose-expansion phase during which 41 patients were treated. All 52 patients were analyzed together.

The researchers report no unexpected toxicities, with three dose-limiting toxicities during the 6-week dose-finding phase. These were a transient ischemic attack in one patient and treatment-related toxicity in two patients (grade 2–3 headache and grade 2 headache, fatigue, asthenia, and dehydration) that led to less than 75% of the planned axitinib dose being completed.

The most common potentially immune-related adverse events, which the researchers say were probably related to pembrolizumab, included diarrhea, increased alanine aminotransferase or aspartate aminotransferase levels, hypothyroidism, and fatigue.

In an accompanying commentary, Giuseppe Procopio (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy) and colleagues say the study “could become the first evidence in favour of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma.”